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Cannabis - Medical Risk Factor

Introduction: Evidence has accumulated suggesting that regular cannabis use is associated with psychotic symptoms and disorders in the general population [1,2] and elevated among incident cases of psychosis [3,4]. In this paper, we present the arguments for, and implications of, considering cannabisuse as a risk factor for psychosis in the 2005Global Burden of Disease (GBD) project.

Introduction: Evidence has accumulated suggesting that regular cannabis use is associated with psychotic symptoms and disorders in the general population [1,2] and elevated among incident cases of psychosis [3,4]. In this paper, we present the arguments for, and implications of, considering cannabisuse as a risk factor for psychosis in the 2005Global Burden of Disease (GBD) project.

Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Australia

Introduction

Evidence has accumulated suggesting that regular cannabis use is associated withpsychotic symptoms and disorders in thegeneral population [1,2] and elevatedamong incident cases of psychosis [3,4].In this paper, we present the arguments for,and implications of, considering cannabisuse as a risk factor for psychosis in the 2005Global Burden of Disease (GBD) project.

Examining Risk Factors forDisease Burden

Governments, policymakers, and fundersneed information on the comparative pop-ulation health impact of different diseasesand risk factors when making decisionsabout where to focus policy, services, andresearch. This field was revolutionised whenthe World Bank provided estimates using the disability-adjusted life year (DALY) [5].This measure combined measures of prema-ture mortality (years of life lost [YLL]) andmorbidity (years lived with disability [YLD])in order to estimate GBD. Estimates of burden attributable to various risk factors— ‘‘comparative risk assessment’’ (CRA) exer-cises[6]—are particularlyimportantbecausethey quantify and allow comparison of theextent to which reduction or removal of exposure to risk factors would reduce diseaseburden by using a measure of estimatedPopulation Attributable Risks (PAR). TheGBD uses fairly standard criteria to evaluate‘‘risk factors’’, in line with Bradford Hill’s [7]oft-quoted criteria (Box 1).

EvidenceontheAssociationbetweenCannabisUseandPsychosis

In the previous global CRA, cannabisuse was not included as a risk factor forany disease because of concerns aboutthe quality of the evidence [8]. In theintervening years there has been a steadyincrease in the number and quality of research studies that have been conductedexploring the links between cannabis useand psychosis. Overall, these studiesindicate that chance is an unlikely expla-nation of their association [9–11]. Recentreviews of prospective general populationstudies of associations between cannabisuse and later psychosis (Table 1) [10,11]concluded that although control for con-founding reduced the size of the associa-tion, there was an increased risk of psychotic outcomes in individuals whoused cannabis, with the greatest risk among those who used cannabis mostfrequently.It is useful to distinguish two primaryways in which cannabis use could be a‘‘cause’’ of psychosis [12]. The strongestform of causal link is that heavy cannabisuse causes a psychosis that would nototherwise have occurred. A second hy-pothesis is that cannabis use is a contrib-utory cause: it might precipitate psychosisin vulnerable individuals—that it is onefactor among many (including geneticpredisposition and other unknown causes)

Research in Translation discusses health interven-tions in the context of translation from basic toclinical research, or from clinical evidence topractice.

2009 Degenhardt et al. This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original author and source are credited.

Funding:

This work was given funding support from the Australian Government Department of Health andAgeing. LD is the recipient of an Australian National Health and Medical Research Council (NHMRC) SeniorResearch Fellowship. The funders had no role in study design, data collection and analysis, decision to publish,or preparation of the manuscript.

Competing Interests:

The authors have declared that no competing interests exist.* E-mail: l.degenhardt@unsw.edu.au

Provenance:

Not commissioned; externally peer reviewed.

Summary

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Comparative risk assessments estimate the proportion of a disease that can beattributed to a particular risk exposure and are important guides for healthplanning.

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In observational studies, there has been consistent evidence that cannabis useis associated with an increased risk of schizophrenia and more generally,psychosis.

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There is debate about whether such observational evidence is sufficient to inferthat cannabis use is a contributory cause of psychosis.

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Given the controversy, should the comparative risk assessment in the currentrevision of the Global Burden of Disease (GBD) include an attribution of psychosis to cannabis use?

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We argue that the risk assessment should be included because the evidence isas good as that for many other risk factors included in the GBD, psychoticdisorders are associated with substantial unavertable disability, and cannabisuse is a potentially preventable exposure.

that act together to cause psychoticdisorders.The evidence suggests that it is morelikely that cannabis use precipitates psy-chosis in vulnerable persons, which isconsistent with other lines of evidencesuggesting that there is a complex constel-lation of factors leading to the develop-ment of psychosis (the stress-diathesismodel of schizophrenia) and with studiessuggesting that gene-environment interac-tions may provide some explanation of theassociation [13]. It is also consistent withconflicting evidence to date on whetherchanges in cannabis use have beenassociated with changes in the incidenceof psychotic disorders in the generalpopulation [14–16].There is also some evidence thatcannabis use is associated with increasedlikelihood of relapse to psychosis among those who have developed a psychoticdisorder [17], although the quality of control for confounding in these studiesis poor [17]. In some studies cannabis usehas also been associated with a youngerage of onset of psychosis [18], althoughcontrol for confounding variables in thesehas also been poor.

Is the Association BiologicallyPlausible?

The principal psychoactive ingredientof cannabis is delta-9-tetrahydrocannabi-nol (THC), which acts upon a specificcannabinoid receptor (CB

1

) in the brain[19]. Although historically the dopaminer-gic system has been considered to play animportant role in psychotic disorders [20],there is increasing evidence that thecannabinoid system may also be involved[21]. Some studies have used animalmodels to explore the impact of THCand related compounds on brain function[21–24]. These results are also stimulating new preclinical research aimed at describ-ing neurobiological mechanisms of actionlinking cannabis and outcomes of interestto schizophrenia [22]. Rodent models arebeing developed to examine the impact of THC exposure on pathways implicated inclinical schizophrenia [21].

What Do We Mean by‘‘Psychosis’’?

Transient cannabis-induced psy-chotic symptoms.

It is possible thatcannabis use might temporarily triggersome symptoms of psychosis among someusers. Such symptoms are clinically (andsignificantly) distinct from a psychoticdisorder such as schizophrenia.Other drugs such as amphetamine havealso been shown to have the potential totrigger psychotic symptoms among someusers [25]. Double-blind provocation stud-ies using intravenous THC and relatedcompounds in healthy controls are pro- viding insights into the neurobiologicalcorrelates of cannabis-related transientpsychotic symptoms and neuro-cognitiveimpairments [26–29].Several cross-sectional studies have ex-amined the relationship between cannabisuse and self-reported psychotic experienc-es or psychotic symptoms in the generalpopulation. All have found that cannabisuse (or cannabis use disorders) were morecommon among people reporting suchexperiences; and these associations persist-ed after controlling for other variables[1,2,12,30]. Although these findings pro- vide important clues to the mechanisms of action linking cannabis use and persistentpsychotic symptoms and/or clinical diag-noses, these outcomes are less of a concernfor the research community.It is not always clear whether thepsychotic symptoms endorsed in studiesassessing the relationship between canna-bis use and ‘‘psychosis’’ occurred only inthe context of cannabis intoxication, orwhether the symptoms were a more distaloutcome of previous cannabis use. Forexample, the Fergusson et al. study [31]assessed the relationship between psychot-ic symptoms in the past month withcannabis use in the past year. It remainspossible that the psychotic symptomsendorsed may have been experienced onlywhile intoxicated. The instruments used tomeasure psychotic outcomes in the Ar-senault et al. [32], Henquet et al. [33], and van Os et al. [34] studies contain instruc-

Box 1. Risk Factor Definitions in the 2005 GBD Project [66]

The GBD defines risks according to the following considerations:

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Risk factors should be potentially modifiable;

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Risks should be assessed irrespective of place in a causal chain or scientificdiscipline that has traditionally analysed the risk factor, as long as evidence of causal effect can be established;

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Risks are defined to be not too broad (e.g., diet or environment as a whole) ortoo narrow (e.g., every single fruit and vegetable or every toxicant in tobaccosmoke) with a relatively specific definition of risk factor exposure;

N

Protective as well as hazardous factors are considered. However, the absence of a specific intervention should not be assessed as a risk factor, but rather inmeasurement of intervention coverage and effectiveness; and

Summary of two systematic reviews investigating cannabis use as a risk factor for psychosis.

Study Details Adjusted Pooled Estimate (95% CI)

Moore et al. [11] Searched Medline, Embase, CINAHL, PsycINFO, ISI Web of Knowledge, ISI Proceedings, ZETOC, BIOSIS,LILACS, and MEDCARIB from their inception to September, 2006; searched reference lists of studiesselected for inclusion; contacted experts. Studies were included if longitudinal and population based.Seven studies were included (some multiple papers). Data extraction and quality assessment weredone independently and in duplicate.Ever use: 1.41 (1.20–1.65)‘‘Heavy’’ use: 2.09 (1.54–2.84)Arsenault et al. [12] The research strategies used were: computerized Medline and PsycLIT searches; cross-referencing of original studies; contact with other researchers in the field. Studies that included a well-defined sampledrawn from population-based registers or cohorts and used prospective measures of cannabis use andadult psychosis.2.34 (1.69–2.95)doi:10.1371/journal.pmed.1000133.t001

tions not to include psychotic symptomsthat only occur in the context of intoxica-tion. Further, the authors of the Swedishconscript study [35] maintain that it isunlikely that substance-induced intoxica-tion would have been misdiagnosed asschizophrenia. We turn now to theevidence relating to more persistent symp-toms or disorders.

Schizophrenia and other psychoticdisorders.

In case-control studies[36,37], patients with schizophrenia aremore likely to use cannabis than otherpsychiatric patients or normal controls[38]. The prevalence of use in patientswith schizophrenia has varied betweenstudies but it is generally higher than ratesin the general population [38,39].Cross-sectional community surveys of psychiatric disorders have also document-ed higher rates of substance use disordersamong persons with schizophrenia [40].Nearly half of the patients identified withschizophrenia in the US ECA study had adiagnosis of substance abuse or depen-dence (28% for an illicit drug disorder)[41,42]. In an Australian population-based survey, 11.5% of those who report-ed that they had been diagnosed withschizophrenia met ICD-10 criteria for acannabis use disorder in the past 12 mo,and 21.2% met criteria for an alcohol usedisorder. After adjusting for confounding variables, those who met criteria forcannabis dependence were 2.9 times morelikely to report that they had beendiagnosed with schizophrenia than thosewho did not [1].The first evidence that cannabis usemay precipitate schizophrenia came froma 15-y prospective study of cannabis useand schizophrenia in 50,465 Swedishconscripts [43]. This study investigatedthe relationship between self-reportedcannabis use at age 18 y and the risk of being diagnosed with schizophrenia in theSwedish psychiatric case register during the next 15 y. Those who had triedcannabis by age 18 y were 2.4 times morelikely to receive a diagnosis of schizophre-nia than those who had not. The risk of adiagnosis of schizophrenia was related tocannabis use in a dose-response way to thenumber of times cannabis had been usedby age 18. Compared to those who hadnot used cannabis, the risk of developing schizophrenia was 1.3 times higher forthose who had used cannabis one to tentimes, three times higher for those whohad used cannabis between one and 50times, and six times higher for those whohad used cannabis more than 50 times.These results remained after statisticaladjustment for two variables that wererelated to the risk of developing schizo-phrenia (personal history of psychiatricdisorder and parental divorce). A number of longitudinal studies havesince been reported that have all support-ed the findings of the Andreassen et al.study. Zammit et al. reported a follow upof the Swedish cohort study, reporting onrisk over a 27-y follow up that covers mostof the risk period for the onset of psychoticdisorders in a cohort that was first studiedwhen 18–20 y old [35]. This study im-proved on the earlier study in a number of ways. The psychiatric register providedmore complete coverage of all casesdiagnosed with schizophrenia; there wasbetter statistical control of a larger numberof potential confounding variables, includ-ing other drug use, IQ, known risk factorsfor schizophrenia, and social integration;the study distinguished between cases thatoccurred in the first 5 y of the study periodand those that occurred more than 5 yafterwards in order to look at the possiblerole of a syndrome; and the studyundertook separate analyses in those whoonly reported using cannabis at the initialassessment.Zammit et al. [35] also found cannabisuse at baseline predicted an increased risk of schizophrenia during the follow-upperiod. There was a dose-response rela-tionship with frequency of use, whichpersisted after statistical control for con-founders, including a history of psychiatricsymptoms at baseline. The same relation-ships were observed in the subset of thesample who only reported cannabis use atbaseline and among cases diagnosed in thefirst 5 y after assessment and for thesubsequent 22 y.Zammit et al.’s findings were consistentwith those of a study conducted by VanOs and colleagues [34]. This was a 3-ylongitudinal study of the relationshipbetween self-reported cannabis use andpsychosis in a community sample of 4,848people in the Netherlands. Participantswere assessed at baseline on cannabis andother drug use. Psychotic symptoms wereassessed using a computerised diagnosticinterview. A diagnosis of psychosis was validated in positive cases by a diagnostictelephone interview with a psychiatrist orpsychologist. A consensus clinical judge-ment was made on the basis of theinterview material as to whether individ-uals had a psychotic disorder for whichthey were in need of psychiatric care.Van Os et al. replicated and extendedthe findings of the Swedish cohort in anumber of important ways. First, cannabisuse at baseline predicted an increased risk of psychotic symptoms during the follow-up period in individuals who had notreported psychiatric symptoms at baseline.Second, there was a dose-response rela-tionship between frequency of cannabisuse at baseline and risk of psychoticsymptoms during the follow-up period.Third, the relationship between cannabisuse and psychotic symptoms persistedwhen they statistically controlled for theeffects of other drug use. Fourth, therelationship between cannabis use andpsychotic symptoms was stronger for caseswith more severe psychotic symptoms thatwere adjudged to need psychiatric care.Fifth, those who reported any psychoticsymptoms at baseline were more likely todevelop schizophrenia if they used canna-bis than were individuals who were not so vulnerable. A study by Henquet et al. [33] replicat-ed the Swedish and Dutch studies in a 4-yfollow up of a cohort of 2,437 adolescentsand young adults between 1995 and 1999in Munich. Their participants were assess-ed at baseline on cannabis use andpsychotic symptoms using a questionnaire.Psychotic symptoms were assessed in earlyadulthood using the Composite Interna-tional Diagnostic Interview. They found adose-response relationship between self-reported cannabis use at baseline and thelikelihood of reporting psychotic symp-toms. As in the Dutch cohort, young people who reported psychotic symptomsat baseline were much more likely toexperience psychotic symptoms at followup if they used cannabis than were peerswho did not have such a history. Arseneault et al. reported a prospectivestudy of the relationship between adoles-cent cannabis use and psychosis in young adults in a New Zealand birth cohort(

n

=759). Participants were assessed inten-sively on risk factors for psychotic symp-toms and disorders since birth [32], andpsychotic disorders were conservativelyassessed according to DSM-IV diagnosticcriteria, with corroborative reports fromfamily members or friends on socialadjustment. They assessed psychoticsymptoms at age 11 y before onset of cannabis use and distinguished betweenearly and late onset of cannabis use. Theyalso examined the specificity of theassociation between cannabis use andpsychosis by conducting analyses of theeffects of: (1) other drug use on psychoticsymptoms and disorders; and (2) cannabisuse on depressive disorders. Arseneault et al. found a relationshipbetween cannabis use by age 15 y and anincreased risk of schizophreniform disor-der by age 26 y. Controlling for otherdrug use did not affect the relationship.